SUMMARY for TR&D 1 Prostate cancer (PCa) is the second leading cause of death from cancer in men in the U.S. The vast majority of men dying of PCa continue to succumb to metastatic castration-resistant disease. There is a compelling need to find effective treatments for metastatic PCa. Our purpose in TR&D1 of the BTRC is to successfully develop prototype theranostic molecular imaging platforms to pursue novel avenues of (i) detecting and targeting the focal adhesion kinase (FAK) mechanotransduction pathway that allow cells to migrate (Aims 1a and b), (ii) detecting and eliminating activated cancer associated fibroblasts (CAFs) that play an important role in the formation of a prometastatic extracellular matrix (ECM) in PCa (Aim 2), and (iii) developing prostate specific antigen (PSMA)-targeted nanoparticles (NPs) to deliver siRNA to downregulate programmed death ligand 1 (PD- L1) together with a prodrug enzyme, to exploit the activation of the immune system, together with localized cell killing, in locally advanced and metastatic PCa (Aim 3). Optical and PET imaging reporters will be integrated into the platforms to achieve spatial and temporal visualization of the NPs in vivo for precision medicine. PSMA, a type II integral membrane protein that is abundantly expressed on the surface of PCa in castration-resistant, advanced and metastatic disease, provides a unique advantage to deliver PSMA-specific NPs for effective control and treatment of locally advanced or metastatic PCa. These studies will result in the accelerated development of FAK PET imaging probes with near term clinical translation that will have a direct impact on the selection of patients for ongoing FAK inhibitor treatment trials. Mechanical movement of cancer cells is a prerequisite for invasion and metastasis. NPs that achieve PCa-specific downregulation of FAK using PSMA- specific delivery will provide cancer-specific downregulation of cell migration, a key step in the metastatic cascade. Similarly, detection of CAFs in tumors with imaging will provide a distinct advantage over biopsy specimens in evaluating CAF numbers as a marker of aggressiveness. CAF elimination with phototherapy may provide a strategy to reduce or eliminate PCa metastasis. The development of NPs to improve immunotherapy in PCa through theranostics and their translation will represent a significant advance in this field since PCa has traditionally not responded well to immunotherapy. TR&D1 will also serve as the Pre-Clinical Validation Core that will, through close interactions with the CPs and other TR&Ds, develop and disseminate novel molecular imaging theranostic agents that will advance precision medicine of cancer worldwide.